Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide. Tumor immune effector and suppressive responses have been linked to improved and poorer clinical responses, respectively. Preliminary data in this proposal demonstrates that hepatic antigen presenting cells (APC) expressing inhibitory B7 family members contribute to the immune suppressive network in human HCC. The long term goal of this project is to define the HCC immune suppressive network and its contribution to HCC progression as well as its therapeutic implications. In addition, biological insight into the function of resident APC subsets within the human liver and interaction with other T cell subsets will translate knowledge to other disease states such as chronic viral hepatitis, autoimmune hepatitis, and transplantation. The overarching hypothesis for this project is that HCC tumor factors promote or recruit inhibitory APC subsets that control the immune suppressive network utilizing inhibitory B7 family member function. This proposal will integrate data obtained from human HCC tissues, peripheral blood, clinical data from HCC patients, and murine models of HCC. The nature of APC subsets, relevance of B7 family members, and mechanisms of their actions in the immune suppressive network will be explored.